Depression and anxiety are common psychiatric illnesses in the U.S. with about 23 million and 28 million people suffering annually. In the1990's, the annual economic burden to society of depressive disorders and anxiety disorders were each estimated at $43 billion dollars.
We aim to understand the neurobiology of """"""""stress vulnerability,"""""""" which leads to anxiety and depressive disorders. Stress is a well known """"""""common factor"""""""" contributing to many disorders. While the causal association with stress is more direct for depressive and anxiety disorders, evidence has accumulated for stress aggravating cardiovascular and inflammatory diseases. Stress responses vary greatly among individuals. This project proposes to explore the mechanism of vulnerability to acute stress. The mouse tail suspension test (TST) reflects these individual differences in behavior to an uncontrollable stressor. This acute stress model has become a facile model of individual differences in stress reactivity (including psychogenic fever/hyperthermia) and antidepressant responses. This project focuses on the genetic factors predisposing to differences in stress responses induced by TST.
The specific aims i nclude: 1) positionally cloning a confirmed locus (Tsti1) on chromosome 5,2) performing secondary and tertiary screens of ENU mutagenized, mutant mice with altered TST behavior, and 3) dissecting the role of gender and cytokines in TST behaviors via selected transgenic mice. The ENU mutant screens will include TST-induced hyperthermia, antidepressant response, and neural activity mapping. Despite the effectiveness of antidepressants, we know little about how these treatments work. The goal is to define robust factors influencing the fundamental biology of individual differences in """"""""stress reactivity,"""""""" favoring assumption free genetic strategies. We hypothesize that the TST paradigm in mice may probe a genetic shared liability for """"""""general distress,"""""""" which is a risk factor for psychiatric disorders. An understanding of the molecular pathophysiology of the mammalian stress response will contribute to integration of established genes and pathways, attach functions to unknown genes, and define new pathways for improved therapy. Ultimately, this work may contribute to our etiological understanding of stress vulnerability, identifying individuals at high risk for stress-induced disorders, and provide rational drug design to sever the link between acute stress and pathological consequences.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Meinecke, Douglas L
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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